1. Field of the Invention
This invention regarding to new C-glycosides which are useful for the treatment and/or prevention of diabetes and a pharmaceutical composition containing these compounds as active ingredients. And this invention is also including the method of preparation of C-glycosides.
Current Technology
The anti-diabetic compounds which modulates energy valance and glucose levels in the body are required recently.
The Na+-glucose cotransporter (SGLT) located on the chorionic membrane of the intestine and the kidney. Glucose is absorbed in the investive and the kidney mediated by SGLT.
The mechanism of inhibiting SGLT provides a novel approach to treat and/or prevent of diabetes. Because the inhibitory effect on SGLT may be excrete extra glucose into urine and as a result, prevent chronic hyperglycemia (Welch, C. A. et al., J.Natr., 1989,119(11)1698).
Phlorizin, O-glycosides, is reported as a specific inhibitor of SGLT. And the series of O-glycosides are synthesized and reported the anti-diabetics activity of these compounds (Hanga, M.et al., Chem.Pharm.Bull.1998,46(1)22, Tokukai 11-021243).
These series of O-glycosides, however, would be cleaved by glycosidase exsists in intestine when orally administrated. 
And it is reported that phloretine, the aglycone of phlorizin, inhibit facilitated-type glucose transporter. For example, intravenously injection of to rats result the reduction of glucose levels in rat brain (Stroke,1983,14,388).
To overcome the stability against glycosidases, acids and bases, the chemistry of C-glycosides which replace of internal oxygen atom to carbone atom are reported (R. J. Linhardt.et al.,Tetrahedron, 1998, 54,9913., D. E. Levy,The Chemistry of C-Glycosides.Pergamon; Oxford,1995., M. H. D. Postema, C-Glycoside Synthesis.CRC Press;Boca Raton.1995). However, it is not reported that C-glycosides has strong SGLT inhibitor, so far.
The Subject of the Invention
The present invention concerns metabolic and hydrolytic stable C-glycosides compounds. These C-glycosides excrete extra glucose into urine and show hypoglycemic activity and a pharmaceutical composition containing these compounds as active ingredients. The present invention also includes the methods of preparing these C-glycosides compounds.
A Solution to the Invention
After elaborated to make C-glycosides which metabolic and hydrolytic stable for an anti-diabetics drug, the inventors found that new compounds as show general formula (I) had shown potent anti-diabetic activities and fulfilled this invention. Namely, the invention is the compounds as shown in general formula (I) and its pharmaceutically acceptable salts and a composition containing these compounds as active ingredients.
A novel C-glycosides and preparation of thereof as the treatment and/or prevention agent of diabetes and the blood glucose lowering agent are provided.
It is that the compounds as shown in general formula (I) and its pharmaceutically acceptable salts.
Namely, the invention is the compounds as shown in general formula (I) and its pharmaceutically acceptable salts and a composition containing those compounds as active ingredients. 
wherein: with the provisos that
R1 is H, OH, lower alkyl, O-lower alkyl or 
R2 is H, xe2x80x94COO-lower alkyl, 
or 
R5 is xe2x80x94CH2OH, xe2x80x94CH2OCO2-lower alkyl, 
xe2x80x94CH2OSO3H, xe2x80x94COOH or xe2x80x94COONa;
wherein: A is 
(with the provisos that X is oxygen atom, nitrogen atom or sulfur atom
R3 is lower alkyl when m=0, and is lower alkyl, xe2x80x94OH or xe2x80x94O-lower alkyl when m=1, . . . means saturated or unsaturated carbon bond;
m is 0 or 1;
n is 0, 1 or 2;
above mentioned-lower alkyl means C1-C5.)
Enforcement of Invention
48 compounds are exemplified as follow, but the invention is not limited to these compounds.
Typical preparations of the compounds of general formula (I) according to the invention are shown, but the invention is not limited to those examples.
The preparations of the compound of general formula (I).
(1) In case of R2 is all hydrogen atoms.
The compounds can be obtained by means of the following diagram (wherein R1, R4, A1, m, and n have the above-mentioned meaning): The compound of general formula (II) is converted to the compound of general formula (I) by the aldol reaction with aldehyde compound of general formula (IV), and followed by the catalytic hydrogenation of double bond of general formula I. 
(2) In case of R1 is xe2x80x94OH, R2 is xe2x80x94H, or xe2x80x94COOCH3.
The compounds can be obtained by means of the following reaction diagrams (wherein A, m, and n have the above-mentioned meaning): The phenolic hydroxy groups of the above-mentioned (I) is protected by allyl group, and then reacted with methyl chloroformate in the presence of base to obtain the compound of general formula (V). After removal of allyl groups of the compound (V) by the Pd catalyst, followed by the catalytic hydrogenation of double bond, if necessary, the compound of general formula (VI) is obtained. 
(3) In case of R1 is xe2x80x94OH, R2 is xe2x80x94H or 
and R5 is 
The compound can be obtained by means of the following reaction diagrams (wherein A and m have the above-mentioned meaning): The compound of general formula (I) is reacted with succinic anhydride in pyridine to obtain the compounds of general formula (XVII) and/or (XVIII). 
(4) In case of R2 is all hydrogen atoms, R5 is CH2OH and R1 is 
The compounds can be obtained by means of the following reaction diagram (wherein A1 and m have the above-mentioned meaning): The phenolic hydroxy group of the compound of general formula (I) is reacted with 4-bromomethyl-5-methyl-1,3-dioxolene in the presence of base, to obtain the compound of general formula (XIX). 
The preparations of the compound of general formula (II).
(a) In case of m=0
The compound can be obtained by means of the following reaction diagram (wherein R1 and n have the above-mentioned meaning, X is halogen (Br, F, etc.), leaving group such as CF3.CO.Oxe2x80x94, and Bn is benzyl): The compound of general formula (VII) is reacted with benzene derivatives (VIII) in the presence of Lewis acid (e.g. BF3.Et2O, SnCl4, AlCl3, AgOSO2CF3 etc.) to synthesize the coupling compound (IX) (e.g. Jaramillo,C.et al.,Synthesis,1994,1) 
And the compound of general formula (IX) can be also obtained by using Grignards reaction of the compound (VII) with Grignards reagent (X) (e.g. Yokoyama,M.et al.,Synthesis,1998,409).
The process is shown in the following reaction diagram. 
(b) In case of m=1
The compound can be obtained by means of the following reaction diagram (wherein R1 and n have the above-mentioned meaning): The compound of general formula (XII) as a starting material is synthesized by the reaction of corresponding lactone (XI) with Tebbe reagent (Tebbe,F. N.,et al.,J.Am.Chem.Soc.,1978,100,3611). The compound of general formula (XII) is hydroborated with 9-borabicyclo[3,3,1]nonane (9-BBN) followed by Suzuki coupling reaction with the compound of general formula (XIII) in the presence of palladium catalyst, to obtain the compound of general formula (XIV) (e.g. Johnson,C. R.et al.,Synlett.,1997,1406). 
And the compound can be obtained by means of the following reaction diagram (wherein R1, X, and n have the above-mentioned meaning): 2,3,4,6-Tetra-O-benzyl-1-thio-xcex2-D-glucopyranose (XX) is reacted with arylmethylhalide (XXI) to convert sulfide (XXII). The oxidation of the compound (XXII) with OXONE(copyright) is led to sulfon (XXIII), and resulting compound (XXIII) is converted to olefin (XXIV) by Ramberg-Bxc3xa4cklund rearrangement reaction. The compound of general formula (XIV) can be aslo synthesized in large scale by the hydrogenation of olefin (XXIV) in the present of palladium catalyst. 
(c) The preparations of the compound of general formula (II)
The compounds can be obtained by means of the following reaction diagram (wherein R1 and n have the above-mentioned meaning): The compounds of general formula (XV) obtained as described above process (a) or (b), is catalytically reducted to debenzylated derivatives, and after acetylation with Ac2O in pyridine, the compound of general formula (XVI) is afforded.
The compound of general formula (II) (in case of R4 is acetyl group) is obtained by the Friedel-Crafts reaction of the compound of general formula (XVI). The compound of general formula (II) (in case of R4 is hydrogen atom) can be also obtained by the subsequent deacetylation with NaOMe. 
And in case of m=1, the compound of general formula (II) can be also obtained as shown in the following reaction diagram (wherein R1, X and n have the above-mentioned meaning): When the Suzuki coupling reaction in above-mentioned process (b) is carried out, in stead of arylhalide (XIII), the derivatives attached acetyl group (XXV) is used to obtain the compound of general formula (XXVI).
Resulting compound can be converted to the compound of general formula (III) or (II) by the debenzylation or followed by acetylation. 
As pharmaceutical acceptable salts of a compound of general formula (I), sodium salt, potassium salt and inorganic base are mentioned.
In case of A1 contains pyridine base, salts of inorganic and organic acids are mentioned. As the salt of inorganic acid, hydrochloride and sulfate are mentioned. As the salt of organic acid, acetate, succinate and fumalate are mentioned.
A compound of general formula (I) can be used itself or formulated to pharmaceutical product such as powder, granule, tablet and capsule by known pharmaceutical technology and can be orally administrable, It can be also administered not orally such as direct administration to rectal and in the form of injection. An effective dosage of the compound is from 10 to 1000 mg once to several times a day for adults, through it may be adjusted depending an age, a body weight and symptoms.
PHARMACOLOGICAL EXPERIMENT
The pharmacological test of urinary glucose excretion in rat is described that follow.
Measurement of Urinary Glucose Excretion in Rats
20 mg of test compounds were dissolved in 10 mL saline containing 20% dimethylsulufoxide.
Test compound (10 mg/5 mL/kg, i.p.) was administered twice an 8 hr interval to male SD rats (6 weeks old, 3 animals/group). An equal volume of vehicle was given to the control group. Urine was collected for 24 hr after first administration in metabolic cages.
The urine was centrifuged and urine volume was measured. Glucose concentration (mg/dl) was assayed using Glucose CII test Wako (Wako Pure Chemicals, Japan). The amounts of glucose excretion during 24 hr was calculated from the following equation.
Glucose secretion (mg/24 hr)=(Axc3x97B)/100
(A; the urine volume, B; the glucose concentration)
The result are shown in Table 8.